SH3BGRL2 inhibits growth and metastasis in clear cell renal cell carcinoma via activating hippo/TEAD1-Twist1 pathway

• Published in: EBioMedicine Vol. 51; p. 102596
• Main Authors: Yin, Lei, Li, Wenjia, Xu, Aiming, Shi, Heng, Wang, Keyi, Yang, Huan, Wang, Ronghao, Peng, Bo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2020; Elsevier
• Subjects: Adult; Aged; Animals; Carcinoma, Renal Cell - etiology; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - mortality; Carcinoma, Renal Cell - pathology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line, Tumor; Cell Movement; Cell Proliferation; Clear cell renal cell carcinoma; Disease Models, Animal; DNA-Binding Proteins - metabolism; Epithelial-Mesenchymal Transition - genetics; Female; Hippo; Humans; Kidney Neoplasms - etiology; Kidney Neoplasms - metabolism; Kidney Neoplasms - mortality; Kidney Neoplasms - pathology; Male; Metastasis; Mice; Middle Aged; Models, Biological; Neoplasm Grading; Nuclear Proteins - metabolism; Prognosis; Protein-Serine-Threonine Kinases - metabolism; Research paper; SH3BGRL2; Transcription Factors - metabolism; Twist-Related Protein 1 - metabolism; Twist1; Xenograft Model Antitumor Assays; PDX; Hippo; ROC; TMA; Clear cell renal cell carcinoma; Metastasis; KIRC; TCGA; CHIP; IVIS; Abbreviations:ccRCC; SH3BGRL2; Twist1
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2019.12.005

Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent malignancies in the world, and tumor metastasis is still the main reason for disease progression. Accumulating evidence shows that SH3BGRL2 may play a key role in tumor progression and metastasis. However, the role of SH3BGRL2 in ccRCC has not been systematically investigated and remains elusive. The clinical significance of SH3BGRL2 was evaluated by bioinformatic analysis and tissue microarray (TMA) samples. SH3BGRL2 expression was determined by RT-PCR, western blot and immunohistochemistry staining. Tumor suppressive effect of SH3BGRL2 was determined by both in vitro and in vivo studies. Western blot, chromatin immunoprecipitation assay and luciferase report assay were applied for mechanism dissection. SH3BGRL2 was crucial for epithelial-mesenchymal transition (EMT) progression and metastasis in ccRCC. Clinically, SH3BGRL2 was identified as an independent prognostic factor for ccRCC patients. Gain- and loss-of-function results suggested that SH3BGRL2 played a critical role in cell proliferation, migration and invasion. Mechanistically, we found that SH3BGRL2 acted as a tumor suppressor through Hippo/TEAD1 signaling, then TEAD1 altered Twist1 expression at the transcriptional level via directly binding to its promoter region. Our findings established that SH3BGRL2 performed as a tumor suppressor and modulator via Hippo/TEAD1-Twist1 signaling in ccRCC, and the alteration of SH3BGRL2 could serve as a functional response biomarker of tumor progression and metastasis in ccRCC.